PROJECT ABSTRACT Hearing loss results from damage to the inner ear, and can lead to degeneration of auditory nerve fibers and anatomic structures central to the peripheral sites of lesion. Importantly, there is growing effort to cure hearing loss using stem cells and other genetic treatments. Unfortunately, clinical diagnostic tests do not specifically identify the location of the insult that creates hearing loss, or describes the physiology of the remaining structures. Thus new diagnostic tests are needed that identify the site(s) of damage so that biologic treatments can be targeted to the specific location. The long term goal of this research is to develop these clinical tests. Patients with hearing loss vary considerably in their perceptual performance as well as their satisfaction with hearing aids and cochlear implants. An important variable in the heterogeneity is illustrated from animal studies and cadaver studies where subjects with similar hearing loss show a variety of anatomic damage. One source of variability is in the population of auditory nerve fibers. Auditory nerve fibers may degenerate in some patients whereas in others a full complement remains. Moreover, a recent finding in an animal model is that even temporary hearing loss, due to loud sound exposure, can cause auditory nerve degeneration without permanent changes in the clinical measures of hearing. This ?hidden hearing loss? along with the degeneration of auditory nerve fibers in patients with hearing loss motivates the research in this proposal to develop a biomarker for auditory nerve survival. The acoustic middle ear muscle (MEM) reflex may serve as an index of auditory nerve survival. The anatomic circuit includes the auditory nerve, and the reflex is sensitive to stretching or compressing the auditory nerve. Measuring the MEM reflex is a standard procedure in Audiology clinics and is used to identify auditory nerve tumors or space-occupying tumors compressing the auditory nerve. The specific aim of this proposal is to determine if the MEM reflex can be used as a biomarker for auditory nerve degeneration. This is accomplished by recording the MEM reflex in an animal model before and after the application of a drug to create neural degeneration. If successful, this biomarker could be used to identify patients with neural degeneration in order to target this site for tissue transplantation. Moreover, determining the extent of neural survival will be useful for predicting successful candidates for cochlear implants and hearing aids, as well as counselling those patients with ?hidden hearing loss?.